Zevalin Radioimmunotherapy is Not Associated with an Increased Incidence of Secondary Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML)

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Zevalin is an anti-CD 20 monoclonal antibody with bonded Yttrium-90, making it a radioimmunotherapy. It is being used more commonly in the treatment of B cell Non Hodgkin's Lymphoma (NHL). NHL therapy has traditionally been treated with alkylating agents with a definite incidence of post-treatment acute myelogenous leukemia (AML) and secondary myelodysplastic syndrome (MDS). Given that Zevalin exposes the patient to radiation, there is concern that Zevalin therapy could result in a high incidence of AML and MDS as well. This study investigated this hypothesis to determine the incidence of AML and MDS in patients treated with Zevalin.

Materials and Methods

770 patients were treated with Zevalin in six clinical trials since 1993, and comprise the patient population.

Patients developing AML or MDS were required to be reported as an adverse event.

Median age of patients was 61 years

Median number of prior therapies was 2, with a range of 0-16

74% of patients had follicular lymphoma

Post-Zevalin bone marrow studies and cytogenic testing were not routinely done in the abscence of symptomatology.

Results

10 out of 770 patients treated with Zevalin over 9 years developed MDS (n=7) or AML (n=3).

The development of MDS or AML was 4-34 months following therapy

Of those patients in whom cytogenetic investigations were performed, all patients displayed abnormalities, most frequently involving chromosomes 5 and 7.

Calculations revealed a 0.62% per person-year incidence of MDS/AML from Zevalin treatment. This compares to a 0.21% per person-year incidence of MDS/AML in those patients with a diagnosis of NHL.

The incidence of MDS/AML with Zevalin therapy does not exceed reports of MDS/AML in NHL patients without previous high-dose therapy (1-1.5% per year).

Author's Conclusions

Zevalin therapy is not associated with an increased incidence of MDS/AML.

Longer follow-up is needed to confirm this.

This information can be used in the future to attempt to identify patients in whom baseline bone marrow ctogenetics will be needed to identify those at risk for MDS/AML.

Clinical/Scientific Implications

Zevalin is a new therapy that has been useful in the treatment of NHL. It uses Y-90 as a beta emitter to deliver doses of radiation to tumor cells, localized to these cells by its CD-20 binding. It delivers 90% of its dose within 5 mm of its binding location. Because of this deposition of radiation, there has been concern about the incidence of secondary AML/MDS. As fludarabine and anthracycline (alkylating) chemotherapy is a common treatment in NHL, there is a known incidence of secondary AML/MDS in these patients. Though the authors claim no increase in incidence of AML/MDS with Zevalin, this claim should be observed with some amount of skepticism. First, although the incidence with Zevalin was not increased when comparing its incidence to historical controls, MDL/AML was three times more common after Zevalin treatment compared to before treatment. Though it can be said that this is simply a reflection of time after initial alkylating treatment, this is not certain. Keeping with time considerations, the authors admit that it may be too early to make conclusions about secondary AML/MDS. Also, classically, the risk of developing secondary problems have been linear with time, so it is certainly possible that the incidence will continue to climb as follow up time increases. Definitive conclusions about all of these issues will likely never be definitively reached, as almost all patients had prior alkylating chemotherapy treatment, it may be an additive effect of chemotherapy + Zevalin, and follow up is never long enough in many cases of (low grade) NHL. What can be ascertained from this study is that the incidence of MDS/AML is not at all high enough to reduce the use of Zevalin as an important treatment modality in patients with NHL. Clearly the overall benefits of Zevalin outweigh the small potential risks.

Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Ortho Biotech.